This project intends to apply methods of theoretical chemistry and statistical methodologies to the study of biomolecular structures and interactions. Systems of interest include the p2l product of the ras oncogene, mammalian p450 enzymes, and the HIV protease. Methods of approach include quantum calculations as well as classical force field approaches, database searching techniques, and molecular graphics. The p2l protein is a molecular "switch" central to a variety of growth and developmental signaling pathways in human tissues. So far, our interest has focused on the catalytic transition from the active or signal transmitting GTP bound to the inactive GDP bound state, with emphasis on the effect of oncogenic mutants on this transition. The available experimental information has left crucial questions unanswered. We are modeling mammalian p450's using the homologous bacterial proteins. These enzymes as a class interact with a wide variety of substrates, and yet their specificity can be finely tuned by specific amino acid substitutions. In the absence of a known structure of a mammalian p450 we are focusing on a geometric model of the binding pocket. The HIV-l protease catalyzes the precise clipping of the polyprotein precursor to the mature viral particle. Its essential role in the viral life cycle has made it the target of intensive inhibitor design efforts. We have begun efforts to apply theoretical approaches to modified metal based inhibitors with the goal of optimizing binding and inhibitory effect.